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Research ArticleArticle

Copper-Dependent Oxidative and Topoisomerase II-Mediated DNA Cleavage by a Netropsin/4′-(9-acridinylamino)methanesulfon-m-anisidide Combilexin

Jean-Pierre Henichart, Michael J. Waring, Jean-Francois Riou, William A. Denny and Christian Bailly
Molecular Pharmacology March 1997, 51 (3) 448-461;
Jean-Pierre Henichart
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Michael J. Waring
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Jean-Francois Riou
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William A. Denny
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Christian Bailly
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Abstract

A conjugate molecule was synthesized by linking the DNA-intercalative antitumor drug 4′-(9-acridinylamino)methanesulfon-m-anisidide (mAMSA) via a 4-carboxamide side chain to a dipyrrolecarboxamide moiety structurally related to the minor groove-binding antibiotic netropsin. The molecule (netropsin/mAMSA) behaves as a threading intercalator. Its netropsin-like tail becomes located in the minor groove of the double helix and serves to drive the hybrid molecule preferentially to AT-rich sites on various DNA fragments as revealed by DNase I footprinting. The hybrid retains the susceptibility to copper-dependent oxidation characteristic of the parent mAMSA moiety as well as its ability to generate oxygen radicals, which can mediate DNA damage, mainly at cytidine and guanosine nucleotides. It also retains the property of stimulating the formation of cleavable complexes with DNA in the presence of topoisomerase II, but its netropsin-like moiety confers little or no influence on the reaction with topoisomerase I. Although netropsin/mAMSA is less potent than mAMSA at producing cleavable complexes with topoisomerase II, it promotes the appearance of cleavage sites at much the same nucleotide sequences as does the parent compound. The dipyrrolecarboxamide tail is not silent, however, since it modifies the concentration-dependence of cleavable complex formation.

Footnotes

  • Send reprint requests to: Dr. Christian Bailly, Institut de Recherches sur le Cancer, INSERM Unité 124, Place de Verdun, 59045 Lille, France. E-mail:bailly{at}lille.inserm.fr

  • ↵1 E. De Clercq, unpublished observations.

  • This work was supported by research grants from Institut National de la Santé et de la Recherche Médicale (C.B.), Ligue Nationale Contre le Cancer (Comité du Nord) (C.B.), Association pour la Recherche sur le Cancer (C.B.), Cancer Research Campaign (M.J.W.), Wellcome Trust (M.J.W.), Association for International Cancer Research (M.J.W.), and Sir Halley Stewart Trust (M.J.W.).

  • Abbreviations:
    mAMSA
    4′-(9-acridinylamino)methanesulfon-m-anisidide (amsacrine)
    bp
    base-pair
    SDS
    sodium dodecyl sulfate
    NetAmsa
    netropsin-4′-(9-acridinylamino)methanesulfon-manisidide
    MPE
    methidiumpropyl-EDTA
    mAQDI
    N1′-methanesulfonyl-N4′-(9-acridinyl)-3′-methoxy-2′,5′-cyclohexadiene-1′,4′-diimine
    mAQI
    3′-methoxy-4′-(9-acridinyl-amino)-2′,5′-cyclohexodiene-1′-one
    • Received July 2, 1996.
    • Accepted October 20, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology
Vol. 51, Issue 3
1 Mar 1997
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Research ArticleArticle

Copper-Dependent Oxidative and Topoisomerase II-Mediated DNA Cleavage by a Netropsin/4′-(9-acridinylamino)methanesulfon-m-anisidide Combilexin

Jean-Pierre Henichart, Michael J. Waring, Jean-Francois Riou, William A. Denny and Christian Bailly
Molecular Pharmacology March 1, 1997, 51 (3) 448-461;

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Research ArticleArticle

Copper-Dependent Oxidative and Topoisomerase II-Mediated DNA Cleavage by a Netropsin/4′-(9-acridinylamino)methanesulfon-m-anisidide Combilexin

Jean-Pierre Henichart, Michael J. Waring, Jean-Francois Riou, William A. Denny and Christian Bailly
Molecular Pharmacology March 1, 1997, 51 (3) 448-461;
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